Paliperidone, or 9-hydroxyrisperidone (chemically: (±)-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3 -yl)-1-piperidinyl)ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one) of the formula (I):
is a major human metabolite of the known antipsychotic drug risperidone and is itself an antipsychotic. It is marketed in tablets for oral administration under the brand name INVEGA™ (Janssen, L. P.) for treatment of schizophrenia. Paliperidone has one centre of optical activity (the carbon in the 9-position); both enantiomers are known but the marketed compound is a racemate.
Paliperidone (including enantiomeric forms thereof) has been disclosed in EP 368388 (U.S. Pat. No. 5,158,952). The same document discloses also esters of paliperidone with carboxylic acids having the formula (II) (R′═C1-19 alkyl)

A preferred ester compound (II) is paliperidone palmitate, which is currently under development for use in injectable compositions with prolonged action.
Various processes for making compounds of formula (I) and (II) have been generally disclosed in the EP 368388 and in later documents. One process is based on an alkylation of a 3-piperidinyl 1,2-benzisoxazole of the formula (2) with the compound of formula (1.1), wherein R is hydrogen or C1-C20 acyl group and A represents an appropriate leaving group such as, for example, halo, e.g., chloro, bromo or iodo; sulfonyloxy, e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, 4-methylbenzenesulfonyloxy and the like leaving groups:

Another known process is based on the reaction of the same compound (1.1) with an oxime compound (3), wherein L is a reactive leaving group, followed by the ring closure of the isoxazole ring on the intermediate (4):

Furthermore, the esters of formula (II) may be prepared by acylating paliperidone (I) by an acylation agent (e.g. acyl halide or acyl anhydride).
The compounds of the general formula (1.1) are valuable intermediates in making paliperidone (I) as well as the paliperidone esters of the formula (II). A typical example of the intermediate of the general formula (1.1) is the compound 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of the formula (1a)

The precise reaction mechanisms including unintended side-reactions, have not, however, been fully elucidated for the above-mentioned reaction schemes. It would be desirable to improve the control, yield, and/or purity of a process for making paliperidone or its esters.